Validation of Sterilizing Grade Filters

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1 Validation of Sterilizing Grade Filters Presented by Laura Okhio-Seaman Sartorius Corporation 1

2 Sterilizing Grade Filters The definition of a sterilizing grade filter is one that will produce a sterile effluent after being challenged by microorganisms at a challenge level of greater than or equal to 1x10 7 /cm 2 of effective filtration area. 2

3 Filter Qualification Tests Physical Tests Flow rates, differential pressure, throughput Sterilizability (SIP, Auto) Integrity tests (bubble point, diffusive flow) Biological Tests Viability Bacterial challenge test Bioburden studies Compendial Tests (USP,EP) Particle release Oxidizable substances Biosafety Endotoxin Other Tests Non-volatile residue Quantitative and qualitative extractables analyses in water and ethanol Leachables testing 3

4 Validation of Sterilizing Grade Filters Demonstrates the filter retains microorganisms to produce a sterile filtrate Ensures the filter does not alter the product in an objectionable way Ensures the product does not adversely affect the filter compatibility Ensures the physical parameters of the process do not adversely affect the filter or the product 4

5 Filter Qualification Tests Viability 5

6 Filter Qualification Tests Brevundimonas diminuta (ATCC 19146) Until the late 1960 s, 0.45 μm-rated membranes were considered sterilizing grade filters, and were used successfully in the sterilizing filtration of parenterals. In the mid-1960 s Dr. Frances Bowman observed a 0.45 μm sterile-filtered culture medium to be contaminated with a micro-organism, subsequently shown to penetrate 0.45 μm-rated membranes repeatedly in small numbers. 6

7 Viability Test Evaluation of potential bactericidal effects of the product solution Viability verified by direct inoculation into product and making serial dilutions Test exposure time should equal or exceed actual process filtration time If less than a one-log reduction (LRV) is observed, product considered non-bactericidal Greater than one-log reduction indicates product is bactericidal and alternatives should be considered 7

8 Viability Test Examples 8

9 Filter Qualification Tests Bacterial Challenge 9

10 Bacterial Challenge Test Filter Qualification by Supplier Challenge Document Bacteria/Water Suspension Stand. Cond. Process-related Filter Validation by User/External Lab Challenge Document Process Cond. Bacteria/Product Suspension 10

11 Bacterial Challenge Test Factors potentially affecting microbial retention include Filter Construction (structure, membrane polymer, pore size distribution) Formulation components Formulation properties (ph, viscosity) Process conditions (time, temperature, pressure differential, flow-rate) 11

12 Bacterial Challenge Test Microbial retention studies on filter devices: Brevundimonas diminuta (ATCC 19146) has been proven to penetrate a 0.45 μm rated filter Spiking of the drug product with Brevundimonas diminuta according to ASTM Challenge level > 10 7 CFUs / cm 2 filtration area. Validation Testing should simulate worst-case process conditions e.g., pressure differential, flow-rate, time, temperature 12

13 Bacterial Challenge Test Challenge suspension should be mono-dispersed to provide worst-case challenge Optical microscopy is used to detect aggregation and clumping of bacteria Ultrasonic treatment reduces aggregation Penetration of 0.45 μm rated membranes is indicative of single-cell conditions and this membrane is used as a positive control 13

14 Bacterial Challenge Test Microscopic investigation Criteria: single cells, motile cells μm μm worst-case 14

15 Bacterial Challenge Test ASTM (2005) uses B. diminuta as the standard challenge organism 2004 Aseptic Processing Guidance suggests the use of native bioburden isolate when appropriate 15

16 Bacterial Challenge Test Microbiological challenge tests using one lot of low Bubble Point (close to manufacturer s minimum specification) membranes should be used. * Example: Minimum Bubble Point Value: Release criteria of filter vendor: Low BP Range: 46 psi 50 psi psi * At or near filter manufacturers minimum integrity test value (10%), 1999 PDA / FDA Joint conference, PDA Newsletter December

17 Filter Medium vs. Device The purpose of the test is to validate the retention efficacy of a particular membrane material. A small 47mm membrane disc can be used To more closely simulate process conditions and to determine the integrity of process filters, a small area 150 or 300 cm 2 filter device capsule can be used Full sized 10 filter cartridges require large volumes of product (25-30 liters) to perform the challenge testing 17

18 Recovery Membrane Selection Either 0.45 or 0.2 micron-rated filter membrane can be used for recovery membranes Studies indicate that 0.45 micron-rated membranes might be more efficient than 0.2 for this purpose Cellulose Nitrate is the preferred membrane polymer high affinity for proteins 18

19 Pressure Differential and Flow Rate Maximum process pressure differentials ( P) across the filter should be used in the challenge studies Process flow-rate should be achieved in challenge studies If pressure and flow rate cannot be simultaneously achieved, the user should determine which is more relevant and develop a rationale to support the decision Regulators tend to prefer higher pressure data rather than flow-rate 19

20 Manual BCT Set-up pressure gauge venting valve venting valve valves test filter capsules analytical disc filters peristaltic pump syringe / sample collection 20 test solution / Brevundimonas diminuta suspension

21 BCT Set-up for Small Scale Pleated Filters 21

22 22 Big Bertha rig Sartorius AG

23 Possible BCT Strategies Determine & Document viability of B. diminuta in Product under Process Conditions Direct inoculation of B. diminuta in product under process conditions VIABLE Is B. diminuta viable in product under process conditions? NOT VIABLE Modify process (adjust temperatures, etc.) Modify formulation (adjust ph, remove bactericidal component or product surrogate) Change from B. diminuta Use bacteria isolated from formulation or environment Use product for time period that the challenge organism is viable Precondition filter with Product followed by Microbial Challenge 23

24 BCT Strategies Method 1 (Direct Inoculation) Determine & Document viability of B. diminuta in Product under Process Conditions Direct inoculation of B. diminuta in product under process conditions VIABLE Is B. diminuta viable in product under process conditions Direct inoculation of B. diminuta in product under process conditions 24

25 BCT Strategies Method 1 (Direct Inoculation) BCT by direct inoculation 25

26 BCT Method 2 (Process Modification) Determine & Document viability of B. diminuta in Product under Process Conditions Direct inoculation of B. diminuta in product under process conditions VIABLE Is B. diminuta viable in product under process conditions? NOT VIABLE Modify process (adjust temperatures, etc.) Modify formulation (adjust ph, remove bactericidal component or product surrogate) Change from B. diminuta Use bacteria isolated from formulation or environment Use product for time period that the challenge organism is viable Precondition filter with Product followed by Microbial Challenge 26

27 BCT Strategies Method 2 (Process Modification) Temperature of 40 C supports mortality rate of B. diminuta Check viability of test bacteria in the product solution at lower temperature Direct inoculation into product solution might be possible at 35 C 27

28 BCT Strategies Method 3 (Time Period Challenge) Determine & Document viability of B. diminuta in Product under Process Conditions Direct inoculation of B. diminuta in product under process conditions VIABLE Is B. diminuta viable in product under process conditions? NOT VIABLE Modify process (adjust temperatures, etc.) Modify formulation (adjust ph, remove bactericidal component or product surrogate) Change from B. diminuta Use bacteria isolated from formulation or environment Use product for time period that the challenge organism is viable Precondition filter with Product followed by Microbial Challenge 28

29 BCT Strategies Method 3 (Time Period Challenge) BCT by direct inoculation 29 Contact time bacteria / test solution max. 30 min.

30 BCT Strategies Method 4 (Formulation Modification) Determine & Document viability of B. diminuta in Product under Process Conditions Direct inoculation of B. diminuta in product under process conditions VIABLE Is B. diminuta viable in product under process conditions? NOT VIABLE Modify process (adjust temperatures, etc.) Modify formulation (adjust ph, remove bactericidal component or product surrogate) Change from B. diminuta Use bacteria isolated from formulation or environment Use product for time period that the challenge organism is viable Precondition filter with Product followed by Microbial Challenge 30

31 BCT Strategies Method 5 (Preconditioning) Determine & Document viability of B. diminuta in Product under Process Conditions Direct inoculation of B. diminuta in product under process conditions VIABLE Is B. diminuta viable in product under process conditions? NOT VIABLE Modify process (adjust temperatures, etc.) Modify formulation (adjust ph, remove bactericidal component or product surrogate) Change from B. diminuta Use bacteria isolated from formulation or environment Use product for time period that the challenge organism is viable Precondition filter with Product followed by Microbial Challenge 31

32 BCT Strategies Method 5 (Preconditioning) Indirect BCT by separate filtration of test solution and bacteria 32

33 BCT Strategies Method 6 (Bioburden Isolate) Determine & Document viability of B. diminuta in Product under Process Conditions Direct inoculation of B. diminuta in product under process conditions VIABLE Is B. diminuta viable in product under process conditions? NOT VIABLE Modify process (adjust temperatures, etc.) Modify formulation (adjust ph, remove bactericidal component or product surrogate) Change from B. diminuta Use bacteria isolated from formulation or environment Use product for time period that the challenge organism is viable Precondition filter with Product followed by Microbial Challenge 33

34 BCT Strategies Method 6 (Bioburden Isolate) BCT with bioburden isolate Reproducible growth and size of bacteria is required Growth in required concentration for BCT must be possible 34

35 Filter Qualification Tests Filter Integrity 35

Integrity Test Correlation Destructive Methods For producers; applied to determined limits: Bacteria-Challenge-Test (according to ASTM) Non-Destructive Methods For users; applied to every sterilizing

36 Integrity Test Correlation Destructive Methods For producers; applied to determined limits: Bacteria-Challenge-Test (according to ASTM) Non-Destructive Methods For users; applied to every sterilizing filter before and after each filtration: Bubble Point Test Diffusion Test Multipoint Diffusion Test Pressure Decay Test Water Intrusion Test (WIT) Direct correlation of diffusion, bubble point, and intrusion-limit values to bacteria-challenge test. 36

37 Integrity Test Correlation 37

38 Bacterial Challenge Test 38

39 Product Wet Integrity Testing Bubble Point Filter membrane is wetted with the product. Pressure is applied on the upstream side of the filter. The pressure at which a stream of air bubbles is detected downstream of the filter is known as the Minimum Bubble Point of the filter. INLET TUBING FROM PRESSURE SOURCE BP TEST Pressure increase PSI POWER CORD SARTOCHECK 3 OUTLET TUBING psi N.I.S.T. TRACEABLE REFERENCE GAUGE BLIND END CAP 39

40 Product Specific Integrity Test Bubble Point e.g. a b c 46 psi PBPmin = 46 psi x 0.73 PBPmin = psi x PBPavg/WBPavg 36 psi/49 psi Flush with Water Test a, b, c Calculate average, WBP avg Flush with Product Test a, b, c PBPmin = WBPmin x Correction Factor Calculate average, PBP avg 40

41 Product Wet Integrity Testing Diffusive Flow Depends mainly on the solubility of the test gas in the wetting fluid in addition to temperature and test pressure. The filter membrane pores are wetted with fluid and a gas pressure less than the BP is applied. Due to differential pressure, gas diffuses through the fluid in the pores and is quantified as downstream flow in ml/min. INLET TUBING FROM PRESSURE SOURCE POWER CORD BP TEST Pressure increase PSI SARTOCHECK 3 OUTLET TUBING psi GRADUATED BURETTE N.I.S.T. TRACEABLE REFERENCE GAUGE BLIND END CAP NOTE: BEAKER AND INVERTED BURETTE MAY BE SUBSTITUTED WITH A N.I.S.T. TRACEABLE MASS FLOWMETER OR ROTAMETER. 41

5 ml/min DF PW /DF WW 16 ml/min/9 /9 ml/min Test a, b, c with MTP WW TP PW = MTP WW x PBP

42 Product Specific Integrity Test Diffusive Flow a b c Flush with Water e.g. 15 ml/min DFL PW = 15 ml/min x 1.77 x DFL PW = 26.5 ml/min DF PW /DF WW 16 ml/min/9 /9 ml/min Test a, b, c with MTP WW TP PW = MTP WW x PBP avg /WBP avg Calculate average, DF WW Flush with Product Test a, b, c with TP PW Calculate average, DF PW DFL PW = DFL WW x Correction Factor 42

43 Integrity Test Failure TR #26 includes a Trouble Shooting Guide in case of Integrity Test Failures: Determines when a filter has to be classified as failed Filter fails first time Measurements & Actions Filter fails second time Wetting with solvent Filter fails third time = Filter failed 43

44 44 Guidance

45 FDA Guidance on Aseptic Processing CGMP Final Guidance released on September 29, 2004, which replaces the 1987 Guidance Describes the integrity test requirements of liquid and air filters, as well as the validation requirements of liquid filters 45

46 FDA Post approval Change Guidance for chemical entities (Revision). Describes which changes in filtration steps are considered moderate (CBE 30) or major (Post Approval Supplement) changes. 46

47 FDA Warning letters and inspection guides are always good to review learn from the mistakes and from the training Listings are posted on FDA website as prescribed by the FOI Act. 47

48 EC Guide to GMP of Sterile Medicinal Products EC cgmp Guidance, Revision of Annex 1. Describes sterilization by filtration, integrity test needs, some validation topics. Important document to know for exporting. 48

49 ISO: AP of Health Care Products Filtration Released ISO Guidance, part 2. on filtration. Describes filtration requirements, validation and integrity test needs thoroughly for liquid and air filters. A good document to have, with thorough descriptions. 49

50 PDA PDA Technical Report #26. The most thorough and descriptive document on the topic of liquid sterilizing filtration. This document is a must have, must read and must understand as it is used by QC and regulators worldwide. 50

Conclusion Regulatory Requirement Industry Requirement Filter Validation Viability Testing Bacterial Challenge Testing Chemical Compatibility

51 Conclusion Regulatory Requirement Industry Requirement Filter Validation Viability Testing Bacterial Challenge Testing Chemical Compatibility Analysis of Extractables Product Integrity Testing Plant and Process Surveys Systems and Integrity Tester Validation Process Related Validation Studies 51

52 Validation of Sterilizing Grade Filters END 52

PDA Technical Report #26:

PDA Technical Report #26: Implications on Liquid Filter Validation Maik W. Jornitz, Sartorius Corp. Filter Qualification Tests for internal Validation Guides Physical Tests flow rates/delta p throughput